Molecular basis of FIR-mediated c-myc transcriptional control

The Far UpStream Element (FUSE) regulatory system promotes a peak in the concentration of c-Myc during cell cycle. First, the FBP transcriptional activator binds to the FUSE DNA element upstream of the c-myc promoter. Then, FBP recruits its specific repressor (FIR) which acts as an on/off transcriptional switch. Here we describe the molecular basis of FIR recruitment showing that the tandem RNA recognitions motifs of FIR provide a platform for independent FUSE DNA and FBP protein binding and explaining the structural basis of the reversibility of the FBP-FIR interaction. We also show that the physical coupling between FBP and FIR is modulated by a flexible linker positioned sequentially to the recruiting element. Our data explain how the FUSE system regulates precisely c-myc transcription and suggest that a small change in FBP–FIR affinity leads to a substantial effect on c-Myc concentration.